CELLULAR MODELS OF ALCOHOL DEPENDENCE USING IN VIVO SYSTEMS

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Our proposed studies are designed to test three major hypothesis: 1. That critical neuronal circuits employing identified transmitters originating from brainstem projection sites, function as a critical indirect components of ethanol's actions of sub-sets of Nacc neurons; 2. That accumbens neurons per se and their intrinsic neurochemical mediators are critical for ethanol reinforcement, dependance and/or relapse; and 3. That a larger tripartite neuronal circuit involving the complex local interactions in the VTA, the amygdala, and sub-divisions of the nucleus accumbens are the critical substrates of ethanol self-administration, dependence and relapse. To further test our hypotheses we will physiologically probe, in vivo, critical components of this pathway. First, identified cells in the anesthetized (halothane) rodent nucleus accumbens shell and core will be assessed as to their response to acutely administered ethanol, and the selective interaction of ethanol with transmitter receptor sub-types utilizing dopamine (DA), gamma-aminobutyric acid (GABA), glutamate and opioids by employing receptor selective agonists and antagonists. Extracellular neurophysiological studies will compare the single cell and multi-synaptic effects of acute alcohol with the actions of alcohol on NAcc neurons following chronic exposure and sustained abstinence. Second, individual cells from regions of the nucleus accumbens, the central nucleus of the amygdala and regions of the ventral tegmental area will be studied simultaneously, in halothane anesthetized rats, for their differential sensitivity to acute ethanol administration and following episodes of dependence and relapse. Finally, we will record spontaneous single unit and macro-physiologic activity from the accumbens in unanesthetized, freely-moving animals during trained ethanol oral self- administration, during ethanol dependence and following prolonged abstinence. In this way we will determine in single unit or macro physiological activity in the accumbens is a predictive cellular correlate of ethanol-seeking behavior and relapse.